The invention relates to a membrane or matrix intended for controlling the permeation rate of a drug, wherein said membrane or matrix comprises a siloxane-based elastomer composition, and to a method for the preparation of said elastomer composition.
Polysiloxanes, in particular poly(dimethyl siloxane) (PDMS), are highly suitable for use as a membrane or matrix regulating the permeation rate of drugs in various drug forms, in particular in implants and IU systems. Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required strength properties.
It is known from the literature that the adding of poly-(ethylene oxide) groups, i.e. PEO groups, to a PDMS polymer may increase the permeation rate of drugs. Publication KL Ullman et al., Journal of Controlled Release 10 (1989) 251-260, describes membranes prepared from a block copolymer which contains PEO and PDMS and the penetration of various steroids through these membranes. It is noted in the publication that an increasing PEO amount in the block polymer tends to increase the penetration of hydrophilic steroids, while the penetration of lipophilic steroids decreases. The block copolymer described in the publication is very complicated in its structure and preparation, and would therefore not be facile in more extensive technical production. Furthermore, said copolymer and thus prepared membrane contains urea groups as well as hydrolyzable urethane groups, of which are undesirable in long-term medical applications as a possible site for degradation or reaction. The process for manufacturing said copolymer, which is also described in U.S. Pat. No. 4,600,751 (see below) uses compounds such as isocyanates, which are toxic and undesirables for environmental and health reasons.
U.S. Pat. No. 4,600,751 discloses an elastomer that cannot be made into a matrix or membrane. According to Tables 1 and 2 of the cited document, when the elastomer composition contains no monomer (Examples 1 and 2, MMA content is 0%), the physical properties of its elastomer are insufficient for such use, indicating in fact that the product obtained in Examples 1 and 2 is not an elastomer. In Table 2, it is shown that it has not been possible to measure for example the tensile strength of the elastomer. The best properties in this respect are achieved when there is 40% of MMA (leading to an elongation at break of 140%), whereas with the elastomers according to the present invention, it is possible to achieve elongations at break in order of 3500 to 4600% at 109 Mpa. Thus, the method in this reference requires the use of additional monomer to crosslink the polymer to form an elastomer. There is no indication that it would be possible to achieve the process according to the present invention by omitting the monomer.
The article xe2x80x9cEffect of polymer composition on steroid permeation: membrane permeation kinetics of androgens and progestinsxe2x80x9d by Sun et al., Journal of Controlled Release, 5 (1987) 69-78, is partly by the same authors as the publication and patent mentioned above. In this document, it is stated that the permeation rate for steroids was higher with PDMS than with PDMS/PEO/PMMA copolymer. It is also stated that the incorporation of PMMA drastically decreases the rate of steroid permeation due to the presence of less permeable xe2x80x9chardxe2x80x9d PMMA domains. Thus, the elastomer described in U.S. Pat. No. 4,600,751 that is crosslinked in the presence of a monomer (styrene, methyl acrylate and methyl (meth)acrylate being given as examples, contains such less permeable domains of for example PMMA. Therefore, in a system as described in U.S. Pat. No. 4,600,751 where monomers are used, said monomers react also with each other thus forming micelles that have a glass transition temperature that is above the body temperature, i.e. above 37xc2x0 C. Typically these polymers have a glass transition temperature that is well above 100xc2x0 C., thus making these polymers rigid at body temperature. This in consequence decreases the permeation rates of active agents.
U.S. Pat. No. 6,013,711 discloses grafted elastomers as well as one two-block elastomer. However, an elastomer comprising both blocks and grafts is not disclosed. These siloxane-polyether copolymers are prepared according to U.S. Pat. No. 6,103,847. The process taught by this patent cannot be used to prepare the multiblock elastomers of the present invention, or for preparing the block-graft-elastomers according to the invention, since the sole examples of polymers having poly(alkylene oxide) blocks are hydroxy-terminated, and thus cannot be crosslinked according to the present invention. The document also fails to disclose crosslinking with peroxide.
The object of the invention is to provide an elastomer composition which is easy to prepare, through which a drug migrates at the desired rate, and which gives the membrane the required mechanical properties.
The object of the invention is in particular to provide an elastomer composition through which the permeation rate of drugs with hormonal action can be controlled.
The invention thus relates to a membrane or matrix for controlling the permeation rate of a drug, the membrane or matrix comprising a siloxane elastomer composition comprising at least one elastomer and optionally a non-crosslinked polymer, wherein the elastomer composition comprises poly(alkylene oxide) groups and the poly(alkylene oxide) groups are present as blocks in a chain of the elastomer or non-crosslinked polymer, or as blocks and alkoxy-terminated grafts of polysiloxane groups, said blocks or blocks and grafts being linked to the polysiloxane groups by silicon-carbon bonds and said elastomer compositions glass transition temperature is less than 35xc2x0 C., with the proviso that there are at least three blocks in the elastomer composition.
The invention also relates to a method for the preparation of a siloxane elastomer, including
a) crosslinking a vinyl-functional polymer component and a hydride-functional siloxane component in the presence of a catalyst and in the absence of monomer, or
b) crosslinking a polymer component in the presence of a peroxide catalyst and in the absence of monomer,
wherein (alkylene oxide) groups are present in the elastomer or polymer as blocks in a chain of said elastomer or polymer, or as blocks and alkoxy-terminated grafts of polysiloxane groups, said blocks or blocks and grafts being linked to polysiloxane groups in said chain by silicon-carbon bonds, there being at least three blocks in said elastomer composition.